The Navajo Nation is home to the largest Native American tribe in the U.S. In the mid 1940's active uranium (U) mining began in the Four Corners region of the southwest U.S. where the Navajo Nation is located. U mining continued for 4 decades until the U ore market collapsed. There are over 1000 unremediated U mines on the Navajo Nation and having not closed these properly has led to widespread U contamination of the soil and water. According to the U.S. EPA there are scores of water sources used by Navajo people for drinking and household use that have U levels that exceed the safe drinking water limit of 30 [unreadable]g/L. There are many health problems known to arise from ingesting U containing water but to date all have to do with the toxicity of U as a heavy metal. Recently we discovered that U, much like other heavy metals, has estrogenic activity. We have found that U, at equimolar concentration to diethylstilbestrol (DES), elicits estrogenic responses in the reproductive tract of female mice and in tissue culture stimulates human breast cancer cell proliferation. In recent experiments we have found that in utero exposure to DES or U causes developing pup ovaries to overproduce androgen compared to ovaries from pups whose dams drank tap water. Based on this new data we propose the hypothesis that in utero U exposure permanently alters the programming of the developing ovary so that it produces more androgen that over a lifetime contributes to premature ovarian failure and metabolic dysregulation. This hypothesis will be tested in two aims. First, we will determine if the hyperandrogenism observed in ovaries from 35-38 day old mice exposed in utero to DES or U is permanent by examining ovaries and analyzing production of androgen in tissue culture from mice up to 18 months of age. And, we will determine if androgen blood levels are increased in these mice during the LH surge of the estrus cycle. In the second aim we will determine if persistent hyperandrogenism contributes to accelerated ovarian failure by short circuiting folliculogenesis. Finally, we will analyze the global effects of lifetime hyperandrogenism by analyzing onset of insulin resistance, hyperglycemia, hypertriglyceridemia and deposition of truncal fat. Our overall goal is to test the hypothesis that in utero exposure to an endocrine disrupting estrogenic chemical, U, leads to increased risk of developing type 2 diabetes and ultimately heart disease. The prevalence of these two chronic illnesses has sky rocketed in the Navajo people in the last several decades. Growing scientific understanding has revealed that the uterine environment as a function of the mother's exposure to environmental chemicals can lead to permanent differences in the developing child that leads to as an adult greater risk for developing diabetes and heart disease. [unreadable] [unreadable] [unreadable]